A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

Mazhor Aldosary; Maysoon Alsagob; Hanan AlQudairy; Ana C. González-Álvarez; Stefan T. Arold; Mohammad Anas Dababo; Omar A. Alharbi; Rawan Almass; Al Bandary AlBakheet; Dalia AlSarar; Alya Qari; Mysoon M. Al-Ansari; Monika Oláhová; Saif A. Al-Shahrani; Moeenaldeen AlSayed; Dilek Colak; Robert W. Taylor; Mohammed AlOwain; Namik Kaya

doi:10.3390/cells11193154

A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

Mazhor Aldosary, Maysoon Alsagob, Hanan AlQudairy, Ana C. González-Álvarez, Stefan T. Arold, Mohammad Anas Dababo, Omar A. Alharbi, Rawan Almass, Al Bandary AlBakheet, Dalia AlSarar, Alya Qari, Mysoon M. Al-Ansari, Monika Oláhová, Saif A. Al-Shahrani, Moeenaldeen AlSayed, Dilek Colak, Robert W. Taylor, Mohammed AlOwain^*, Namik Kaya^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G<T, p.Val159Phe) in the gene. Clinically affected individuals presented with intellectual disability, encephalopathy, ataxia, optic atrophy, and seizures. Based on whole exome sequencing and confirmatory Sanger sequencing, the variant was fully segregated with the phenotype in the families, absent among large ethnically matching controls as well as numerous in-house exomes, and predicted to be pathogenic by different in silico classifiers. Structural modeling and immunoblot analyses strongly indicated this variant to be pathogenic. Since the families belong to one of the tribal inhabitants of Saudi Arabia, we postulate that the variant is likely to be a founder. We provide the estimated age of the variant and present data confirming the disease-causality of this founder variant.

Original language	English (US)
Article number	3154
Journal	Cells
Volume	11
Issue number	19
DOIs	https://doi.org/10.3390/cells11193154
State	Published - Oct 2022

Bibliographical note

Funding Information:
This research was funded by King Salman Center for Disability Research (KSCDR grant number #2180-004). The research from STA and ACC-A was supported by the King Abdullah University of Science and Technology (KAUST) through the baseline fund and the Award No. FCC/1/1976-25 and REI/1/4446-01 from the Office of Sponsored Research (OSR). R.W.T. is funded by the Welcome Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. MO and RWT are funded by the Pathological Society.

Publisher Copyright:
© 2022 by the authors.

Keywords

age of variant
encephalopathy
founder variant
in silico pathogenicity prediction
missense
optic atrophy
RTN4IP1
structural modeling

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.3390/cells11193154

Cite this

Aldosary, M., Alsagob, M., AlQudairy, H., González-Álvarez, A. C., Arold, S. T., Dababo, M. A., Alharbi, O. A., Almass, R., AlBakheet, A. B., AlSarar, D., Qari, A., Al-Ansari, M. M., Oláhová, M., Al-Shahrani, S. A., AlSayed, M., Colak, D., Taylor, R. W., AlOwain, M., & Kaya, N. (2022). A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families. Cells, 11(19), Article 3154. https://doi.org/10.3390/cells11193154

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title = "A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families",

abstract = "The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G",

keywords = "age of variant, encephalopathy, founder variant, in silico pathogenicity prediction, missense, optic atrophy, RTN4IP1, structural modeling",

author = "Mazhor Aldosary and Maysoon Alsagob and Hanan AlQudairy and Gonz{\'a}lez-{\'A}lvarez, {Ana C.} and Arold, {Stefan T.} and Dababo, {Mohammad Anas} and Alharbi, {Omar A.} and Rawan Almass and AlBakheet, {Al Bandary} and Dalia AlSarar and Alya Qari and Al-Ansari, {Mysoon M.} and Monika Ol{\'a}hov{\'a} and Al-Shahrani, {Saif A.} and Moeenaldeen AlSayed and Dilek Colak and Taylor, {Robert W.} and Mohammed AlOwain and Namik Kaya",

note = "Funding Information: This research was funded by King Salman Center for Disability Research (KSCDR grant number #2180-004). The research from STA and ACC-A was supported by the King Abdullah University of Science and Technology (KAUST) through the baseline fund and the Award No. FCC/1/1976-25 and REI/1/4446-01 from the Office of Sponsored Research (OSR). R.W.T. is funded by the Welcome Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. MO and RWT are funded by the Pathological Society. Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = oct,

doi = "10.3390/cells11193154",

language = "English (US)",

volume = "11",

journal = "Cells",

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Aldosary, M, Alsagob, M, AlQudairy, H, González-Álvarez, AC , Arold, ST, Dababo, MA, Alharbi, OA, Almass, R, AlBakheet, AB, AlSarar, D, Qari, A, Al-Ansari, MM, Oláhová, M, Al-Shahrani, SA, AlSayed, M, Colak, D, Taylor, RW, AlOwain, M & Kaya, N 2022, 'A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families', Cells, vol. 11, no. 19, 3154. https://doi.org/10.3390/cells11193154

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T1 - A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

AU - Aldosary, Mazhor

AU - Alsagob, Maysoon

AU - AlQudairy, Hanan

AU - González-Álvarez, Ana C.

AU - Arold, Stefan T.

AU - Dababo, Mohammad Anas

AU - Alharbi, Omar A.

AU - Almass, Rawan

AU - AlBakheet, Al Bandary

AU - AlSarar, Dalia

AU - Qari, Alya

AU - Al-Ansari, Mysoon M.

AU - Oláhová, Monika

AU - Al-Shahrani, Saif A.

AU - AlSayed, Moeenaldeen

AU - Colak, Dilek

AU - Taylor, Robert W.

AU - AlOwain, Mohammed

AU - Kaya, Namik

N1 - Funding Information: This research was funded by King Salman Center for Disability Research (KSCDR grant number #2180-004). The research from STA and ACC-A was supported by the King Abdullah University of Science and Technology (KAUST) through the baseline fund and the Award No. FCC/1/1976-25 and REI/1/4446-01 from the Office of Sponsored Research (OSR). R.W.T. is funded by the Welcome Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. MO and RWT are funded by the Pathological Society. Publisher Copyright: © 2022 by the authors.

PY - 2022/10

Y1 - 2022/10

N2 - The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G

AB - The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G

KW - age of variant

KW - encephalopathy

KW - founder variant

KW - in silico pathogenicity prediction

KW - missense

KW - optic atrophy

KW - RTN4IP1

KW - structural modeling

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U2 - 10.3390/cells11193154

DO - 10.3390/cells11193154

M3 - Article

C2 - 36231115

AN - SCOPUS:85139951178

SN - 2073-4409

VL - 11

JO - Cells

JF - Cells

IS - 19

M1 - 3154

ER -

A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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